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12
L. E. Enny et al.
after the exposure. In a systemic review and meta-analysis, the overall exposure to
diagnostic radiation was associated with a signicantly increased risk of thyroid
cancer [12].
A family history of thyroid cancer has been associated with a tenfold
increased risk of non-medullary thyroid cancer. The familial risk for papillary
carcinoma was 3.21 and 6.24, respectively, in a population-based study when
a parent and a sibling were diagnosed with thyroid cancers [13]. Familial differentiated thyroid cancer may also arise as part of cancer syndrome, including Werner syndrome, Cowden’s, FAP syndrome, and Carney complex. A
substantial risk factor for malignancy is a personal or family history of MEN2
or FMTC.
Clinical Diagnosis: Diagnosis of a thyroid nodule is based on three criteria,
namely anatomical features, hormonal prole and cytological features. The clinical
examination helps to underscore the probability of a solitary nodule, multinodularity or diffuse enlargement apart from xity to neighbouring structures and
enlarged lymph nodes. Routinely performed estimation of thyrotropin (TSH) and
Free Thyroxine (FT4) categorises the hormonal status to overt hyperthyroidism,
subclinical hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism and
euthyroid state.
The nature of the pathology of thyroid nodules can broadly be classified
into three types: benign, suspicious of malignancy, or malignant. Combining
the above three parameters leads to diagnosis (Figs.2.1 and 2.2). Suffixes like
cervical lymph node palpable and retrosternal extension can be added. The
further evaluation of hormonal profile, radiological features or fine needle
aspiration cytology is based on this concept, which is why it is called a triple
assessment.
Fig. 2.1 Diagnosis (CAP)
of thyroid nodule
Hormonal:
Euthyroid
Hypothyroid
Hyperthyroid
Anatomical:
Solitary
Multinodular
Diffuse
± Retrosternal
Pathological:
Benign
suspicious
malignant
2 Solitary Thyroid Nodule
13
Hormonal
Functional status
Euthyroid/Hypothyroidism/Hyperthyroidism
Anatomy
Morphology
(Solitary/Multinodular/Diffuse)
Pathology
Benign/Malignant
Fig. 2.2 Diagnostic work up of thyroid nodule
•TSH
•Thyroid scanonlyinbiochemicallytoxicnodules
•Imaging (PreferablyhighResolutionUltrasound
Neck)
•Chest X- Ray,NeckXRay,CTscanNeck
• FNACorpreferably(Palpatoryguided)
• TruCutbiopsytobedoneveryrarely
2.5 Serum Thyrotropin andThyroid Hormones
The rst laboratory investigation that should be obtained in a patient with thyroid nodule during initial evaluation is serum thyrotropin as its value will indicate whether the
nodule is hyperfunctioning, which is seen in 10% of all nodules [14], hypo functioning
or iso-functioning. When serum thyrotropin is subnormal, a free thyrotropin and total
or free triiodothyronine should be measured apart from a radionuclide scan to document the functional status of the nodule. When the serum thyrotropin value is higher
than the normal reference range, anti-thyroid peroxidase (anti-TPO) antibodies may be
measured to evaluate for the presence of autoimmune (Hashimoto) thyroiditis [15].
2.6 Serum Thyroglobulin
Measurement of thyroglobulin in postoperative monitoring of residual, recurrent or
metastatic disease in differentiated thyroid cancer may be helpful. But values may
also be elevated even in many benign thyroid disorders (e.g. multinodular goitre,
thyroiditis). A routine measurement of thyroglobulin at initial thyroid nodule evaluation is not recommended.
2.7 Serum Calcitonin
Calcitonin is produced by parafollicular C cells of the thyroid and is a marker for
medullary thyroid carcinoma (MTC). Although routine evaluation of calcitonin
may detect early MTC or C-cell hyperplasia at an early stage, there is no sufcient
14
L. E. Enny et al.
evidence to support that early detection reduces MTC-specic mortality. Recent
guidelines do not recommend routine measurement of calcitonin [3]. Calcitonin
measurement should be considered in the subgroup of patients whose elevated value
may change the diagnostic or surgical approach. These include patients with a family history of MTC or MEN 2 syndrome and patients with suspicious cytology not
consistent with papillary thyroid carcinoma (PTC). If measured, an unstimulated
calcitonin level of >100pg/mL suggests medullary thyroid cancer (sensitivity of
60% and specicity of 100%) [16].
2.8 Radiological Evaluation
2.8.1 Thyroid Ultrasonography
High-resolution ultrasonography (US) is the imaging modality for thyroid nodules.
Diagnostic neck ultrasound should be performed in all patients presenting with palpable thyroid nodules or thyroid nodules that are incidentally diagnosed on another
imaging study like computed tomography (CT), magnetic resonance imaging
(MRI), or PET CT.It is the primary tool for the initial stratication of cancer risk in
thyroid nodules and guides FNA decision-making. US report should include a
description of thyroid parenchyma (homogenous or heterogenous), size of the
gland, size, location and sonographic features of the nodule including composition
(cystic, solid or spongiform), echogenicity, margin, presence of calcications, vascularity and shape and helps in assessing cervical lymph nodes. The sonographic
features suggesting malignancy include hypoechogenicity, solid composition, taller
than wider orientation, and the presence of microcalcication/broken rim calcication inltrative or irregular margin [17, 18]. A combination of criteria in the US are
used to predict the risk of malignancy in thyroid nodules, and no single measure is
entirely accurate in diagnosing or predicting malignancy [18].
A Thyroid Imaging Reporting and Data System (TIRADS) has been developed on
the lines of BIRADS in the breasts to predict malignancy in a thyroid nodules. Many
distinct TIRAD guidelines have been described to classify thyroid nodules as benign
or malignant and to recommend for or against ne needle aspiration biopsy (FNAB)
of the thyroid nodule (Table2.1) [16–19]. The American Thyroid Association (ATA)
has classied the nodule into high suspicious, intermediate suspicious, low suspicious, shallow suspicious and benign categories based on US features (Table2.2).
The American College of Radiology (ACR) recommends a point system based
on ve US features for systematic assessment for imaging a thyroid nodule. The
sum of all the points determines the Thyroid Imaging Reporting and Data System
(ACR-TIRADS) classication of thyroid nodules, their estimated risk of thyroid
cancer and recommendations for FNAC or surveillance [17]. The total number of
points is then used to classify nodules into TR1 (benign), TR2 (not suspicious), TR3
(mildly suspicious), TR4 (moderately suspicious), TR5 (highly suspicious) categories with probability of malignancy of 0, 3.4, 14, and 87% in categories 2, 3, 4 and
5 respectively (Tables 2.2 and 2.3).
2 Solitary Thyroid Nodule
Table 2.1 TIRADS categories based on ACR-TIRADS, K-TIRADS AND EU-TIRADS with
their expected prevalence of malignancy (POM) and thyroid FNAB threshold [16, 17, 19]
System
ACR-
TIRADS
K-TIRADS Composition,
EU-TIRADS Composition,
K-TIRADS Korean Society of Thyroid Radiology Thyroid Imaging Reporting and Data System;
ACR-TIRADS American College of Radiology TIRADS; EU TIRADS European Union TIRADS
USG pattern based on TIRADS Categories POM %
Composition,
echogenicity, shape,
margin, echogenic foci
echogenicity, presence
of suspicious features
echogenicity, and risk
factors
1 Benign <2% No biopsy
2 Not suspicious <2% No biopsy
3 Mildly
suspicious
4 Moderately
suspicious
5 Highly
suspicious
1 No nodule – No biopsy
2 Benign <3%
3 Low
suspicious
4 Intermediate
suspicious
5 High
suspicious
1 Normal 0 –
2 Benign 0 No FNA
3 Low risk 2–4% >2cm
4 Intermediate
risk
5 High risk 26–87% >1cm
5%
5–20%
>20%
3–15%
15–50%
>60%
6–17% >1.5cm
FNAB
threshold
≥2.5cm
≥1.5cm
≥1cm
≥ 2cm
≥1.5cm
≥1cm
≥1cm
(>0.5cm,
selective)
15
Table 2.2 Risk classication of thyroid nodules based on ultrasound patterns as described by
American Thyroid Association
Risk categories
Characteristics Solid, hypoechoic or
Risk of
harbouring
malignancy
High Intermediate Low
Hypoechoic
partially cystic nodule
with irregular margin
(inltrative, micro
lobulated) or taller than
wider shape or
micro-calcications or
broken rim calcication
or extra-thyroidal
extension
Up to 90% Between 10
solid nodule
and 20%
Isoechoic or
hyperechoic
solid nodule, or
partially cystic
nodule with
eccentric solid
areas
Between 5 and
10%
Very low
Spongiform
or partially
cystic
nodules
Less than 3%
16
L. E. Enny et al.
Table 2.3 The ACRTIRADS scoring system of
reporting for thyroid nodules
US features Points
Composition Cystic or almost completely cystic 0
Spongiform 0
Mixed cystic and solid 1
Solid or almost completely solid 2
Echogenicity Anechoic 0
Hyper or isoechoic 1
Hypoechoic 2
Very hypoechoic 3
Shape Wider than tall 0
Taller than wide 3
Margin Smooth 0
Ill-dened 0
Lobulated or irregular 2
Extrathyroidal extension 3
Echogenic
foci
None or large comet tail artefact 0
Macrocalcication 1
Peripheral rim calcication 2
Punctate echogenic foci 3
2.8.2 Radioisotope Imaging
Radioisotope scanning has been used to assess the functional status of the nodule into:
1. Hyperfunctioning nodule (‘hot’, i.e. tracer uptake more signicant than the surrounding tissue);
2. Hypo functioning nodule (‘cold’, i.e. tracer uptake less than the surrounding
tissue); and
3. Iso functioning (‘warm’, uptake equal to surrounding thyroid tissue).
However, it does not determine the size of the thyroid nodule. The isotopes used
for imaging are technetium (99mTc), (123I), and (121I). Hot nodules account for
5%, with the likelihood of malignancy <1%. About 80–85% of thyroid nodules are
cold, and about 10% may harbour malignancy [20].
2.9 CT andMRI
Generally, CT and MRI are not part of evaluating thyroid nodules and are only helpful in particular situations. These imaging are functional when thyroid cancer is
suspected to invade neighbouring structures or encase the carotid artery or is found
to have bulky lymph node metastases. When a primary mediastinal goitre or mediastinal extension is suspected, CT is useful in assessing the extent of the lesion and
compression of the trachea. Contrast-enhanced CT should be employed cautiously
2 Solitary Thyroid Nodule
in malignancy since iodine loading will induce stunning and delay the radioiodine
treatment when indicated. Radioiodine ablation is usually delayed for 1–2months
when contrast-enhanced CT is done preoperatively.
17
2.10 18F-Fluorodeoxyglucose Positron Emission Computed
Tomography (18F-FDG-PET/CT)
Although imaging with 18F-FDG PET/CT is not currently recommended during the
initial workup of thyroid nodules, there is growing evidence that PET imaging is an
important tool, and its use may inuence the clinical management of differentiated
thyroid disease. Its use has been widely accepted in detecting recurrent DTC.The
emerging role of 18F-FDG PET/CT in thyroid nodules is attributed to the clinical
experience of incidentally detected FDG focal thyroid uptake on PET/CT performed
for unrelated non-thyroidal purposes [21]. Use of 18F-FDG PET/CT has also been
shown to increase the diagnostic accuracy, especially in patients with thyroid nodule with indeterminate cytology. Vriens and colleagues have reported the pooled
sensitivity, specicity, NPV, and positive predictive value of FDG-PET were 95%,
48%, 96% and 39%, respectively. A positive FDG-PET scan increases the possibility of malignancy in these patients from 25.8 to 38.7% [22].
2.11 Cytological Evaluation
Aspiration cytology has emerged as the most critical decision-making tool in managing thyroid nodules.
FNAC biopsies provide the most valuable, cost-effective and denitive diagnostic information for evaluating thyroid nodules. It is considered the most reliable
technique in differentiating malignant from benign thyroid nodules. Studies have
shown that even in the experienced hands, the rate of non-contributory reports may
reach up to 10% [23]. The reported crude sensitivity and specicity were 65–98%
and 72–100%, respectively [24]. Smaller lesions (<10 mm) and larger lesions
(>30mm) may have 1–5% negative reports [25]. but a targeted aspiration reduces
the issue to some extent. Another hindrance is the more signicant cystic components (25–50%) and the nodules placed in the posterior aspects of the lobes [26].
Previously, the cytology reports were confusing and were not reasonably translated to routine practical management. A standardised reporting system was introduced in 2007, popularly referred to as (Bethesda System for Reporting Thyroid
Cytopathology) and was recently revised in 2016.
Over the past few years, to address the variability and standardise the reporting
of thyroid cytopathology, a criteria system (Bethesda System for Reporting Thyroid
Cytopathology) was introduced in 2007 and revised in 2016.
Bethesda system of reporting broadly categorises the nodules into six categories and an estimated risk of malignancy in each type is now known [27–29]
(Table2.4). The newer recommendations elaborate on the possible management
18
Table 2.4 Risk of malignancy in rst and second editions of the Bethesda System for Reporting
Thyroid Cytopathology
Risk of
Bethesda
classication
1 Nondiagnostic or unsatisfactory
2 Benign
3 AUS/FLUS
4 FN/SFN
5 Suspicious for malignancy
6 Malignant 97–99 97–99
Diagnostic category
• Cyst uid only
• Obscuring blood
• Insufcient number of follicular
cells
• Follicular nodule (adenomatoid
and colloid nodule)
• Chronic lymphocytic thyroiditis
• Granulomatous thyroiditis
• Focal nuclear atypia
• Microfollicular pattern in a
hypocellular specimen
• Predominance of Hurthle cells
• Crowded and overlapping
follicular cells some or most of
which are arranged as micro
follicles
• Subtle and focal nuclear and
architectural changes of
malignancy
malignancy, rst
edition %
1–4 5–10
0–3 0–3
5–15 10–30
15–30 25–40
60–75 50–75
L. E. Enny et al.
Risk of
malignancy,
second edition %
protocol for the indeterminate category of cytology. The updated classication of
thyroid cancers has recognised a new variety of non-invasive follicular thyroid
neoplasms with papillary- like nuclear features (NIFTP), which is thought to represent an early stage of invasive encapsulated follicular variant of papillary cancer with shallow malignant potential [3]. Besides this system, there are UK and
Italian categorisations of FNAC reporting, but they are not as popular as the
Bethesda system (Table2.5). In the case of patients with multi-nodular goitre,
aspiration is generally done from nodules >10mm in size with suspicious features on ultrasound imaging or from a cold nodule on scintigraphy.
2 Solitary Thyroid Nodule
Table 2.5 Comparison of the Italian AME Consensus, UK-RC Path and Bethesda systems for
classication and reporting of thyroid ne needle aspiration cytology results
Italian Consensus, 2014
TIR 1. Non-diagnostic
TIR 1c. Nondiagnostic cystic
TIR 2. Non-malignant Thy 2. Non-neoplastic II: Benign
TIR 3A.Low-risk
indeterminate lesion
TIR 3B.High-risk
indeterminate lesion
TIR 4. Suspicious for
malignancy
TIR 5. Malignant Thy 5. Malignant V.Suspicious for malignancy
– – VI.Malignant
UK-RC path
Thy 1. Non-diagnostic
Thy 1c. Unsatisfactory,
consistent with cyst
Thy 3a. Neoplasm possible:
atypia
Thy 3f. Neoplasm possible:
suggestive of follicular
neoplasm
Thy 4. Suspicious for
malignancy
Bethesda system
I: Non-diagnostic or cystic
III: AUS/FLUS atypia or follicular
lesion of undetermined
signicance
IV.Follicular neoplasm or
suspicious for follicular neoplasm
19
2.12 Molecular Assessment
There is still a grey area in managing thyroid nodules with Bethesda III and IV
cytological features, otherwise called the indeterminate category. The routine practice is to do a repeat aspiration under guidance. If cytological study remains noncontributory and ultrasound features are suspicious, a diagnostic lobectomy was
resorted to.
After the genetic changes in differentiated thyroid cancers were established,
molecular testing was incorporated into aspiration studies, which improved diagnostic accuracy. The new studies are broadly known as rule-in studies, indicating
the possibility of cancer, and rule-out studies, which may exclude chances of cancer.
The rule in tests include mutation analysis of set genes in the aspirated cells, a
seven-gene panel (BRAF, H-RAS, N-RAS, K-RAS, RET/PTC1, RET/PTC3, PAX8/
PPARy) along with P53 and TERT gene. The presence of a mutation in BRAF,
TERT, and P53 is consistently associated with thyroid cancer. The seven gene panel
was found to have 95% specicity but a poor sensitivity (48%).
The two most common molecular tests are mutation analysis and gene expression analysis. Mutation analysis or testing also termed a rule in test analysis mutation in several genes, including the seven gene panel (BRAF, H-RAS, N-RAS,
K-RAS, RET/PTC1, RET/PTC3, PAX8/PPARy) along with P53 and TERT gene.
The presence of a mutation in BRAF, TERT, and P53 is consistently associated with
thyroid cancer. In a large prospective study on 513 nodules with Bethesda III, IV,
and V cytology, the sensitivity and specicity were 63% and 99%, respectively [30].
There are many commercially available comprehensive packages for molecular study.
1. The Arma gene expression classier (GEC) is a rule-out test panel and
examines 167 genes associated with thyroid cancer [31]. The test panel was
recently updated from a microarray mRNA platform to next-generation RNA
20
L. E. Enny et al.
sequencing, which utilises (NGS) platform. Thyroid nodules with Bethesda
III and IV cytological features shall be observed if the GEC panel shows
benign results.
2. The Thyroid Sequencing test (ThyroSeq) is a rule-in test protocol based on
detecting cancer-associated molecular alterations in cell D3NA and RNA.The
version included a 7-gene panel (mutations-BRAF, N-/H-/K-RAS, translocations RET/PTC and PAX8/PPAR), but the 2013 version included a 13-gene
panel. ThyroSeq v2, 2014 version has a 56-gene panel analysing additional point
mutations and gene fusions. The 2017 version of ThyroSeq v3 includes more
than 12,000 mutation hotspots and 120 gene fusion types. Now, this panel has an
improved sensitivity and specicity in detecting all types of thyroid cancers. In
a prospective blinded multicentre study by Steward etal., ThyroSeq v3 demonstrated a sensitivity of 91%, specicity of 85%, PPV of 64% and NPV of 97% in
Bethesda III nodules and sensitivity of 97%, specicity of 75%, PPV of 68% and
NPV 98% in Bethesda IV nodules [31].
3. ThyGenX is a targeted NGS test that assays for mutations in ve genes (BRAF,
KRAS, HRAS, NRAS, and PIK3CA) and three gene fusions (RET-PTC1, RETPTC3, and PAX8-PPARG) associated with thyroid cancers.
4. ThyraMIR measures the expression levels of ten microRNAs (miRNAs) and
gives a risk-based classication of the nodule based on the miRNA prole.
2.13 Decision-Making andManagement
Management of the patients with thyroid nodules depends on various factors,
including size of the nodule, symptomatology, ultrasound and FNAC ndings and
patient’s choice. Generally, surgery is recommended in patients with compressive
symptoms, hyper-functioning nodules and nodules with suspicious or proven malignancy. For patients with unilateral compressive nodule and of benign cytology,
hemithyroidectomy is preferred and for those with bilateral compressive goitre,
total-thyroidectomy is recommended.
For a non-diagnostic nodule based on Bethesda classication, repeat
ultrasound- guided FNAC is advised and preferably within 3–6months to avoid
a false positive result, and if it again comes out non-diagnostic, patients can be
either kept on close follow-up with clinical assessment and ultrasound periodically or should be considered for thyroid lobectomy based on patient’s preference and if the nodule shows high suspicious features on ultrasound (Figs.2.3
and 2.4).
For those patients kept on follow-up, thyroid lobectomy is recommended if
the nodule growth is >20% in two dimensions and >50% increase in volume.
Patients with benign cytology should be kept on close follow-up with periodic
2 Solitary Thyroid Nodule
Clinical riskassessmentfor
increased malignantPotential
High resolution
Ultrasound
Spongiform
Cystic
Historyofhead,neckradiation,
Family HofMTC,PTC,MENII
Malesex,Age<14or>70years,Shortduration,
Rapid growth,RecentVoicechange,
Persistentdysphonia,dyspnea,
FirmtoHardconsistency
Fixed Nodule,CervicalLymphadenopathy
Suspicious features
Mixedcystic/solid
±AbnormalLNs
±Elevatedstiffness
21
ThyroidNodule
Fine Needle
Aspiration Cytology
Very Low
CONSERVATIVE
Low
Intermediate
High
SURGERY
Very High
Fig. 2.3 Algorithm of work up and management of thyroid nodule
clinical and ultrasound evaluations. The interval for repeat USG may be adjusted
based on the USG risk group. For those with high sonographic suspicion, repeat
ultrasound should be done within 3–6 months and repeat FNAB within
12 months. For nodules with low or intermediate suspicion for malignancy,
repeat USG should be repeated within 12–24months. For nodules with very low
suspicion, frequent repeat USG is not usually needed but may be repeated after
2years or whenever a patient is symptomatic or if there is an increase in the size
of the nodule. On repeat ultrasound, if the nodule shows >50% change in volume or >20% increase in two dimensions, repeat FNA, preferably USG guided,
is advised [3].
These guidelines and recommendations must also take into account the patient’s
preference. In a remote area where the follow-up is not so robust and if the patient
desire surgery due to fear of malignancy, thyroid lobectomy or total thyroidectomy
can be offered depending on the clinical risk factors, sonographic features, number
and site of involvement.
If the cytology is suspicious or malignancy (Bethesda 5 and 6), the preferred or
recommended management is hemi or total thyroidectomy ± lymph node dissection
depending on the clinical risk factor, sonographic features and molecular testing.
Small intrathyroidal nodules of <1cm could undergo active surveillance (Figs.2.5
and 2.6) [32].